This invention relates to pharmaceutical compositions comprised of amorphous dispersions of drugs and neutral polymers that provide either improved chemical stability, concentration-enhancement, or both improved chemical stability and concentration-enhancement.
It is sometimes desired to form a solid amorphous dispersion of a drug and a polymer. One reason for forming dispersions is that the aqueous concentration of a poorly soluble drug may be improved by forming an amorphous dispersion of the drug and a polymer. For example, Curatolo, et al., EP 0 901 786 A2 disclose forming pharmaceutical spray dried dispersions of sparingly soluble drugs and the polymer hydroxypropyl methyl cellulose acetate succinate. The spray dried dispersions disclosed in Curatolo et al. provide superior aqueous concentration relative to dispersions formed from other methods and relative to the crystalline drug alone.
Similarly, others have recognized the enhancement in aqueous concentration afforded by dispersing a drug in a polymer. Nakamichi, et al., U.S. Pat. No. 5,456,923 disclose solid dispersions formed by twin-screw extrusion of low solubility drugs and various polymers.
Another reason for forming an amorphous dispersion is that it may be desired to use a particular process for forming a pharmaceutical composition, such as a spray-coating or wet granulation process which results in the formation of amorphous drug, in whole or in part, rather than pure crystalline drug. Thus, amorphous dispersions may be formed of drugs which are not low-solubility drugs.
However, regardless of whether the drug is poorly soluble, the inventors have determined that for some drug and polymer dispersions, the drug is not chemically stable in the dispersion. In particular, the inventors have observed that for dispersions containing certain drugs and polymers, the drug degrades in the dispersion over time, resulting in a loss of potency for the composition. The inventors have found this problem to arise especially for acid-sensitive drugs.
Drug degradation within the dispersion is a particular problem for low-solubility, acid-sensitive drugs, since the increase in aqueous concentration of the drug provided by the dispersion is offset by decreasing drug purity. In general, the greatest concentration-enhancement is often observed through the use of acidic dispersion polymers, especially acidic, cellulosic enteric polymers. However, the use of such acidic polymers within the dispersion is precluded due to the acid-sensitive nature of the drug.
Accordingly, there is still a need for pharmaceutical compositions of dispersions containing acid-sensitive drugs that are chemically stable over time. Likewise, there is also a continuing need to provide concentration-enhancement for low-solubility drugs.